dose-escalation study of oral administration of s 055746 in patients with acute myeloid leukaemia or myelodysplastic syndrome

Conditions: Acute Myeloid Leukaemia (AML); Myelodysplastic Syndrome (MDS)

Summary: the purpose of this study is to determine the safety profile and tolerability of s 055746 in patients with aml, and high or very high risk mds, in terms of dose-limiting toxicities (dlts), maximum tolerated dose (mtd) and determine the recommended phase 2 dose (rp2d) through safety profile (dlt, mtd), pk profile, pd profile and preliminary efficacy.


Eligibility criteria:
inclusion criteria: * women or men aged \>= 18 years * patients with cytologically confirmed and documented de novo, secondary or therapy-related aml excluding acute promyelocytic leukaemia: * with relapsed or refractory disease or * \> or = 65 years not previously treated for aml, who are not candidates for intensive chemotherapy or not candidates for standard chemotherapy * patients with cytologically confirmed and documented mds or non proliferative chronic myelomonocytic leukaemia (cmml) in relapse or refractory after previous treatment line including at least one hypomethylating agent therapy: * with high or very high risk mds and without established alternative therapy * transformed to aml and without established alternative therapy * ability to swallow oral tablet(s) * world health organization (who) performance status 0-2 * circulating white blood cells \< or = 30 x 10\^9 /l and \< or = 13 x10\^9 for non proliferative cmml * adequate renal and hepatic functions * negative serum pregnancy test within 7 days prior to the first day of study drug administration * patients must use effective contraception * written informed consent exclusion criteria: * foreseeable poor compliance to the study procedures * legally incapacitated person under guardianship or trusteeship * pregnant or breast-feeding women * participation in therapeutic interventional study involving investigational drug intake at the same time or within 2 weeks or at least 5 half-lives or patient already enrolled * previous treatment with a bh3 mimetic * patients who have not recovered to baseline or ctcae\< or = grade 1 from toxicity due to all prior therapies received for the studied disease * any previous anti-leukaemic treatment for the studied disease within at least 5 half-lives or 2 weeks (hydroxycarbamide permitted) * any radiotherapy within 4 weeks before first intake (except palliative radiotherapy at localized lesions) * major surgery within 3 weeks before first intake of s 055746 * allogenic stem cell transplant within 6 months before the first intake of s 055746 and for patients who still need immunosuppressive treatment * leukaemic leptomeningeal or leukaemic central nervous system involvement * concomitant uncontrolled infection, organ dysfunction or medical disease likely to interfere with evaluation of s 055746 safety or study outcome * human immunodeficiency virus (hiv) infection, hepatitis b or active hepatitis c infection * within 6 months prior to the first intake of s 055746, history of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting, ischemic/haemorrhagic stroke, atrial fibrillation, digestive haemorrhagic risk, deep venous/arterial thromboembolic complication or bleeding diathesis * decreased left ventricular ejection fraction (lvef) * qtcf prolongation * patients who are receiving qt prolonging drug * coagulopathies with increased risk of bleeding complications * other malignancy within 2 years prior to the first intake * strong or moderate cyp3a4 inhibitors or inducers (treatment, food or drink products) within 7 days prior to the first intake * treatment highly metabolised by the cyp3a4 or cyp2d6 and/or with a narrow therapeutic index, multi-enzymes and/or oatp and/or p-gp substrates or herbal products within 7 days prior to the first intake. * patients receiving proton pump inhibitor * patients having received anticoagulant oral drugs, aspirin \> 325 mg/day and antiplatelets within 7 days prior to first s 055746 intake